Microporous zirconium silicate for the treatment of hyperkalemia

ABSTRACT

The present invention relates to novel microporous zirconium silicate compositions that are formulated to remove toxins, e.g. potassium ions, from the gastrointestinal tract at an elevated rate without causing undesirable side effects. The preferred formulations are designed avoid increase in pH of urine in patients and/or avoid potential entry of particles into the bloodstream of the patient. Also disclosed is a method for preparing high purity crystals of UZSi-9 exhibiting an enhanced level of potassium exchange capacity. These compositions are particularly useful in the therapeutic treatment of hyperkalemia.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation of U.S. patent application Ser. No.13/371,080, filed Feb. 10, 2012, which claims priority to U.S.Provisional Patent Application No. 61/441,893, filed Feb. 11, 2011, thecontents of each are hereby incorporated by reference in theirentireties.

BACKGROUND OF THE INVENTION

(i) Field of the Invention

The present invention relates to novel microporous zirconium silicatecompositions that are formulated to remove toxins, e.g., potassium ionsor ammonium ions, from the gastrointestinal tract at an elevated ratewithout causing undesirable side effects. The preferred formulations aredesigned to avoid potential entry of particles into the bloodstream andpotential increase in pH of urine in patients. These compositions areparticularly useful in the therapeutic treatment of hyperkalemia. Alsodisclosed are microporous zirconium silicate compositions havingenhanced purity and potassium exchange capacity (KEC), and methods andapparatus for making such microporous zirconium silicate compositions.

(ii) Description of the Related Art

Acute hyperkalemia is a serious life threatening condition resultingfrom elevated serum potassium levels. Potassium is a ubiquitous ion,involved in numerous processes in the human body. It is the mostabundant intracellular cation and is critically important for numerousphysiological processes, including maintenance of cellular membranepotential, homeostasis of cell volume, and transmission of actionpotentials. Its main dietary sources are vegetables (tomatoes andpotatoes), fruit (oranges, bananas) and meat. The normal potassiumlevels in plasma are between 3.5-5.0 mmol/l with the kidney being themain regulator of potassium levels. The renal elimination of potassiumis passive (through the glomeruli) with active reabsorption in theproximal tubule and the ascending limb of the loop of Henle. There isactive excretion of potassium in the distal tubules and the collectingduct, both of which processes are controlled by aldosterone.

Increased extracellular potassium levels result in depolarization of themembrane potential of cells. This depolarization opens somevoltage-gated sodium channels, but not enough to generate an actionpotential. After a short period of time, the open sodium channelsinactivate and become refractory, increasing the threshold to generatean action potential. This leads to impairment of the neuromuscular-,cardiac- and gastrointestinal organ systems, and this impairment isresponsible for the symptoms seen with hyperkalemia. Of greatest concernis the effect on the cardiac system, where impairment of cardiacconduction can lead to fatal cardiac arrhythmias such as asystole orventricular fibrillation. Because of the potential for fatal cardiacarrhythmias, hyperkalemia represents an acute metabolic emergency thatmust be immediately corrected.

Hyperkalemia may develop when there is excessive production of serumpotassium (oral intake, tissue breakdown). Ineffective elimination,which is the most common cause of hyperkalemia, can be hormonal (as inaldosterone deficiency), pharmacologic (treatment with ACE-inhibitors orangiotensin-receptor blockers) or, more commonly, due to reduced kidneyfunction or advanced cardiac failure. The most common cause ofhyperkalemia is renal insufficiency, and there is a close correlationbetween degree of kidney failure and serum potassium (S-K) levels. Inaddition, a number of different commonly used drugs cause hyperkalemia,such as ACE-inhibitors, angiotensin receptor blockers, potassium-sparingdiuretics (e.g. amiloride, spironolactone), NSAIDs (such as ibuprofen,naproxen, celecoxib), heparin and certain cytotoxic and/or antibioticdrugs (such as cyclosporin and trimethoprim). Finally, beta-receptorblocking agents, digoxin or succinylcholine are other well-known causesof hyperkalemia. In addition, advanced degrees of congestive heartdisease, massive injuries, burns or intravascular hemolysis causehyperkalemia, as can metabolic acidosis, most often as part of diabeticketoacidosis.

Symptoms of hyperkalemia are somewhat non-specific and generally includemalaise, palpitations and muscle weakness or signs of cardiacarrhythmias, such as palpitations, brady-tachycardia ordizziness/fainting. Often, however, the hyperkalemia is detected duringroutine screening blood tests for a medical disorder or after severecomplications have developed, such as cardiac arrhythmias or suddendeath. Diagnosis is obviously established by S-K measurements.

Treatment depends on the S-K levels. In milder cases (S-K between 5-6.5mmol/l), acute treatment with a potassium binding resin (Kayexalate®),combined with dietary advice (low potassium diet) and possiblymodification of drug treatment (if treated with drugs causinghyperkalemia) is the standard of care; if S-K is above 6.5 mmol/l or ifarrhythmias are present, emergency lowering of potassium and closemonitoring in a hospital setting is mandated. The following treatmentsare typically used:

-   -   Kayexalate®, a resin that binds potassium in the intestine and        hence increases fecal excretion, thereby reducing S-K levels.        However, as Kayexalate® has been shown to cause intestinal        obstruction and potential rupture. Further, diarrhea needs to be        simultaneously induced with treatment. These factors have        reduced the palatability of treatment with Kayexalate®.    -   Insulin IV (+glucose to prevent hypoglycemia), which shifts        potassium into the cells and away from the blood.    -   Calcium supplementation. Calcium does not lower S-K, but it        decreases myocardial excitability and hence stabilizes the        myocardium, reducing the risk for cardiac arrhythmias.    -   Bicarbonate. The bicarbonate ion will stimulate an exchange of        K+ for Na+, thus leading to stimulation of the sodium-potassium        ATPase.    -   Dialysis (in severe cases).

The only pharmacologic modality that actually increases elimination ofpotassium from the body is Kayexalate®; however, due to the need toinduce diarrhea, Kayexalate® cannot be administered on a chronic basis,and even in the acute setting, the need to induce diarrhea, combinedwith only marginal efficacy and a foul smell and taste, reduces itsusefulness.

The use of zirconium silicate or titanium silicate microporous ionexchangers to remove toxic cations and anions from blood or dialysate isdescribed in U.S. Pat. Nos. 6,579,460, 6,099,737, and 6,332,985, each ofwhich is incorporated herein in their entirety. Additional examples ofmicroporous ion exchangers are found in U.S. Pat. Nos. 6,814,871,5,891,417, and 5,888,472, each of which is incorporated herein in theirentirety.

The inventors have found that known zirconium silicate compositions mayexhibit undesirable effects when utilized in vivo for the removal ofpotassium in the treatment of hyperkalemia. Specifically, theadministration of zirconium silicate molecular sieve compositions hasbeen associated with an incidence of mixed leukocyte inflammation,minimal acute urinary bladder inflammation and the observation ofunidentified crystals in the renal pelvis and urine in animal studies,as well as an increase in urine pH. Further, known zirconium silicatecompositions have had issues with crystalline impurities and undesirablylow cation exchange capacity.

The inventors have discovered novel zirconium silicate molecular sievesto address the problem associated with existing hyperkalemia treatments,and novel methods of treatment for hyperkalemia utilizing these novelcompositions.

SUMMARY OF THE INVENTION

Zirconium silicate and zirconium germanate molecular sieves have amicroporous structure composed of ZrO₃ octahedral units and at least oneSiO₂ tetrahedral units and GeO₂ tetrahedral units. These molecularsieves have the empirical formula:A_(p)M_(x)Zr_(1-x)Si_(n)Ge_(y)O_(m)  (I)where A is an exchangeable cation selected from potassium ion, sodiumion, rubidium ion, cesium ion, calcium ion, magnesium ion, hydronium ionor mixtures thereof, M is at least one framework metal selected from thegroup consisting of hafnium (4+), tin (4+), niobium (5+), titanium (4+),cerium (4+), germanium (4+), praseodymium (4+), and terbium (4+), “p”has a value from about 1 to about 20, “x” has a value from 0 to lessthan 1, “n” has a value from about 0 to about 12, “y” has a value from 0to about 12, “m” has a value from about 3 to about 36 and 1≦n+y≦12. Thegermanium can substitute for the silicon, zirconium or combinationsthereof. Since the compositions are essentially insoluble in bodilyfluids (at neutral or basic pH), they can be orally ingested in order toremove toxins in the gastrointestinal system.

In one embodiment, the composition exhibits median particle size ofgreater than 3 microns and less than 7% of the particles in thecomposition have a diameter less than 3 microns. Preferably, less than5% of the particles in the composition have a diameter less than 3microns, more preferably less than 4% of the particles in thecomposition have a diameter less than 3 microns, more preferably lessthan 3% of the particles in the composition have a diameter of less than3 microns, more preferably less than 2% of the particles in thecomposition have a diameter of less than 3 microns, more preferably lessthan 1% of the particles in the composition have a diameter of less than3 microns, more preferably less than 0.5% of the particles in thecomposition have a diameter of less than 3 microns. Most preferably,none of the particles or only trace amounts have a diameter of less than3 microns.

The median and average particle size is preferably greater than 3microns and particles reaching a sizes on the order of 1,000 microns arepossible for certain applications. Preferably, the median particle sizeranges from 5 to 1000 microns, more preferably 10 to 600 microns, morepreferably from 15 to 200 microns, and most preferably from 20 to 100microns.

In one embodiment, the composition exhibiting the median particle sizeand fraction of particles in the composition having a diameter less than3 micron described above also exhibits a sodium content of below 12% byweight. Preferably, the sodium contents is below 9% by weight, morepreferably the sodium content is below 6% by weight, more preferably thesodium content is below 3% by weight, more preferably the sodium contentis in a range of between 0.05 to 3% by weight, and most preferably 0.01%or less by weight or as low as possible.

In one embodiment, the invention involves a pharmaceutical productcomprising the composition in capsule or tablet form.

In one embodiment, a molecular sieve is provided which has an elevatedcation exchange capacity, particularly potassium exchange capacity. Theelevated cation exchange capacity is achieved by a specialized processand reactor configuration that lifts and more thoroughly suspendscrystals throughout the reaction. In an embodiment of the invention, theUZSi-9 crystals had a potassium exchange capacity of greater than 2.5meq/g, more preferably greater than 3.5 meq/g, more preferably greaterthan 4.0 meq/g, more preferably between 4.3 and 4.8 meq/g, even morepreferably between 4.4 and 4.7 meq/g, and most preferably approximately4.5 meq/g. UZSi-9 crystals having a potassium exchange capacity in therange of 3.7-3.9 were produced in accordance with Example 13 below.

The compositions of the present invention may be used in the treatmentof hyperkalemia comprising administering the composition to a patient inneed thereof. The administered dose may vary, depending on whether thetreatment is for chronic or acute hyperkalemia. The dose for treatingacute hyperkalemia is higher than that for the treatment of chronichyperkalemia. For the treatment of acute hyperkalemia, the dosepreferably ranges from approximately 0.7 to 1,500 mg/Kg/day, morepreferably from approximately 500 to 1,000 mg/Kg/day, and mostpreferably approximately 700 mg/Kg/day. A typical daily dose fortreatment of acute hyperkalemia, depending on the potassium exchangecapacity, in a human patient will range from approximately 50 mg to 60 gper day, more preferably from approximately 1 mg to 30 g per day, morepreferably 3 to 9 g per day, and most preferably approximately 3 g perday. For the treatment of chronic hyperkalemia, the dose preferablyranges from 0.25 to 100 mg/Kg/day, more preferably from 10 to 70mg/Kg/day, and most preferably approximately 50 mg/Kg/day. A typicaldaily dose for treatment of chronic hyperkalemia in a human patient willrange from approximately 0.020 to 10 g per day, more preferably from 0.1to 1 g per day, and most preferably approximately 0.5 g per day.

For higher KEC compositions, the dosages will typically be lower due tothe increased effectiveness of the compositions for lowering potassiumlevels in a patient. For the treatment of acute hyperkalemia, the dosepreferably ranges from approximately 0.7 to 800 mg/Kg/day, morepreferably from approximately 280 to 500 mg/Kg/day, and most preferablyapproximately 390 mg/Kg/day. A typical daily dose for treatment of acutehyperkalemia, depending on the potassium exchange capacity, in a humanpatient will range from approximately 50 mg to 33 g per day, morepreferably from approximately 1 mg to 30 g per day, more preferably 3 to9 g per day, and most preferably approximately 3 g per day. For thetreatment of chronic hyperkalemia, the dose preferably ranges from 0.25to 55 mg/Kg/day, more preferably from 5 to 40 mg/Kg/day, and mostpreferably approximately 30 mg/Kg/day. A typical daily dose fortreatment of chronic hyperkalemia in a human patient will range fromapproximately 0.020 to 5 g per day, more preferably from 0.05 to 0.7 gper day, and most preferably approximately 0.5 g per day.

Compositions of the invention may be prepared by subjecting a zirconiumsilicate composition as described above to screening or a combination ofscreening and ion exchange processes as further described herein.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a polyhedral drawing showing the structure of microporouszirconium silicate Na_(2.19)ZrSi_(3.01)O_(9.11).2.71H₂O (MW 420.71)

FIG. 2 shows particle size distribution of ZS-9 lot 5332-04310-A inaccordance with Example 8.

FIG. 3 shows particle size distribution of ZS-9 lot 5332-15410-A inaccordance with Example 8.

FIG. 4 shows particle size distribution of ZS-9 preclinical lot inaccordance with Example 8.

FIG. 5 shows particle size distribution of lot 5332-04310A w/o screeningin accordance with Example 9.

FIG. 6 shows particle size distribution of lot 5332-04310A 635 mesh inaccordance with Example 9.

FIG. 7 shows particle size distribution of lot 5332-04310A 450 mesh inaccordance with Example 9.

FIG. 8 shows particle size distribution of lot 5332-04310A 325 mesh inaccordance with Example 9.

FIG. 9 shows particle size distribution of lot 5332-04310A 230 mesh inaccordance with Example 9.

FIG. 10: XRD plot for ZS-9 prepared in accordance with Example 12.

FIG. 11: FTIR plot for ZS-9 prepared in accordance with Example 12.

FIG. 12: XRD plot for ZS-9 prepared in accordance with Example 13.

FIG. 13: FTIR plot for ZS-9 prepared in accordance with Example 13.

FIG. 14: Example of the Blank Solution Chromatogram

FIG. 15: Example of the Assay Standard Solution Chromatogram.

FIG. 16: Exemplary Sample Chromatogram.

FIG. 17: Reaction vessel with standard agitator arrangement.

FIG. 18: Reaction vessel with baffles for production of enhanced ZS-9

FIG. 19: Detail of baffle design for 200-L reaction vessel forproduction of enhanced ZS-9

DETAILED DESCRIPTION OF THE INVENTION

The inventors have discovered novel zirconium silicate molecular sieveabsorbers that address problems of adverse effects in the therapeuticuse of molecular sieve absorbers, e.g., for the treatment ofhyperkalemia. Zirconium silicate has a microporous framework structurecomposed of ZrO₂ octahedral units and SiO₂ tetrahedral units. FIG. 1 isa polyhedral drawing showing the structure of microporous zirconiumsilicate Na_(2.19)ZrSi_(3.01)O_(9.11).2.71H₂O (MW 420.71) The darkpolygons depict the octahedral zirconium oxide units while the lightpolygons depict the tetrahedral silicon dioxide units. Cations are notdepicted in FIG. 1.

The microporous exchanger of the invention has a large capacity andstrong affinity, i.e., selectivity, for potassium or ammonium. Eleventypes of zirconium silicate are available, UZSi-1 through UZSi-11, eachhaving various affinities to ions have been developed. See e.g., U.S.Pat. No. 5,891,417. UZSi-9 (otherwise known as ZS-9) is a particularlyeffective zirconium silicate absorber for absorbing potassium andammonium. These zirconium silicates have the empirical formula:A_(p)M_(x)Zr_(1-x)Si_(n)Ge_(y)O_(m)  (I)where A is an exchangeable cation selected from potassium ion, sodiumion, rubidium ion, cesium ion, calcium ion, magnesium ion, hydronium ionor mixtures thereof, M is at least one framework metal selected from thegroup consisting of hafnium (4+), tin (4+), niobium (5+), titanium (4+),cerium (4+), germanium (4+), praseodymium (4+), and terbium (4+), “p”has a value from about 1 to about 20, “x” has a value from 0 to lessthan 1, “n” has a value from about 0 to about 12, “y” has a value from 0to about 12, “m” has a value from about 3 to about 36 and 1≦n+y≦12. Thegermanium can substitute for the silicon, zirconium or combinationsthereof. It is preferred that x and y are zero or both approaching zero,as germanium and other metals are often present in trace quantities.Since the compositions are essentially insoluble in bodily fluids (atneutral or basic pH), they can be orally ingested in order to removetoxins in the gastrointestinal system.

The zirconium metallates are prepared by a hydrothermal crystallizationof a reaction mixture prepared by combining a reactive source ofzirconium, silicon and/or germanium, optionally one or more M metal, atleast one alkali metal and water. The alkali metal acts as a templatingagent. Any zirconium compound, which can be hydrolyzed to zirconiumoxide or zirconium hydroxide, can be used. Specific examples of thesecompounds include zirconium alkoxide, e.g., zirconium n-propoxide,zirconium hydroxide, zirconium acetate, zirconium oxychloride, zirconiumchloride, zirconium phosphate and zirconium oxynitrate. The sources ofsilica include colloidal silica, fumed silica and sodium silicate. Thesources of germanium include germanium oxide, germanium alkoxides andgermanium tetrachloride. Alkali sources include potassium hydroxide,sodium hydroxide, rubidium hydroxide, cesium hydroxide, sodiumcarbonate, potassium carbonate, rubidium carbonate, cesium carbonate,sodium halide, potassium halide, rubidium halide, cesium halide, sodiumethylenediamine tetraacetic acid (EDTA), potassium EDTA, rubidium EDTA,and cesium EDTA. The M metals sources include the M metal oxides,alkoxides, halide salts, acetate salts, nitrate salts and sulfate salts.Specific examples of the M metal sources include, but are not limited totitanium alkoxides, titanium tetrachloride, titanium trichloride,titanium dioxide, tin tetrachloride, tin isopropoxide, niobiumisopropoxide, hydrous niobium oxide, hafnium isopropoxide, hafniumchloride, hafnium oxychloride, cerium chloride, cerium oxide and ceriumsulfate.

Generally, the hydrothermal process used to prepare the zirconiummetallate or titanium metallate ion exchange compositions of thisinvention involves forming a reaction mixture which in terms of molarratios of the oxides is expressed by the formulae:aA₂O:bMO_(q/2):1−bZrO₂ :cSiO₂ :dGeO₂ :eH₂Owhere “a” has a value from about 0.25 to about 40, “b” has a value fromabout 0 to about 1, “q” is the valence of M, “c” has a value from about0.5 to about 30, “d” has a value from about 0 to about 30 and “e” has avalue of 10 to about 3000. The reaction mixture is prepared by mixingthe desired sources of zirconium, silicon and optionally germanium,alkali metal and optional M metal in any order to give the desiredmixture. It is also necessary that the mixture have a basic pH andpreferably a pH of at least 8. The basicity of the mixture is controlledby adding excess alkali hydroxide and/or basic compounds of the otherconstituents of the mixture. Having formed the reaction mixture, it isnext reacted at a temperature of about 100° C. to about 250° C. for aperiod of about 1 to about 30 days in a sealed reaction vessel underautogenous pressure. After the allotted time, the mixture is filtered toisolate the solid product which is washed with deionized water, acid ordilute acid and dried. Numerous drying techniques can be utilizedincluding vacuum drying, tray drying, fluidized bed drying. For example,the filtered material may be oven dried in air under vacuum.

To allow for ready reference, the different structure types of thezirconium silicate molecular sieves and zirconium germanate molecularsieves have been given arbitrary designations of UZSi-1 where the “1”represents a framework of structure type “1”. That is, one or morezirconium silicate and/or zirconium germanate molecular sieves withdifferent empirical formulas can have the same structure type.

The X-ray patterns presented in the following examples were obtainedusing standard X-ray powder diffraction techniques and reported in U.S.Pat. No. 5,891,417. The radiation source was a high-intensity X-ray tubeoperated at 45 Kv and 35 ma. The diffraction pattern from the copperK-alpha radiation was obtained by appropriate computer based techniques.Flat compressed powder samples were continuously scanned at 2° (2θ) perminute. Interplanar spacings (d) in Angstrom units were obtained fromthe position of the diffraction peaks expressed as 2 θ where θ is theBragg angle as observed from digitized data. Intensities were determinedfrom the integrated area of diffraction peaks after subtractingbackground, “I_(o)” being the intensity of the strongest line or peak,and “I” being the intensity of each of the other peaks.

As will be understood by those skilled in the art, the determination ofthe parameter 20 is subject to both human and mechanical error, which incombination can impose an uncertainty of about ±0.4 on each reportedvalue of 20. This uncertainty is, of course, also manifested in thereported values of the d-spacings, which are calculated from the 0values. This imprecision is general throughout the art and is notsufficient to preclude the differentiation of the present crystallinematerials from each other and from the compositions of the prior art. Insome of the X-ray patterns reported, the relative intensities of thed-spacings are indicated by the notations vs, s, m and w which representvery strong, strong, medium, and weak, respectively. In terms of100×I/I_(o), the above designations are defined as w=0-15; m=15-60;s=60-80 and vs=80-100.

In certain instances the purity of a synthesized product may be assessedwith reference to its X-ray powder diffraction pattern. Thus, forexample, if a sample is stated to be pure, it is intended only that theX-ray pattern of the sample is free of lines attributable to crystallineimpurities, not that there are no amorphous materials present.

The crystalline compositions of the instant invention may becharacterized by their X-ray powder diffraction patterns and such mayhave one of the X-ray patterns containing the d-spacings and intensitiesset forth in the following Tables. The x-ray pattern for ZS-11 asreported in U.S. Pat. No. 5,891,417, is as follows:

TABLE 1 UZSi-11 d(Å) I 6.0-6.8 w-m 5.5-6.3 m 5.4-6.2 vs 5.2-6.0 m2.7-3.5 s 2.5-3.3 mThe x-ray diffraction pattern for the high-purity, high KEC ZS-9 as madein accordance with Example 13 herein (XRD shown in FIG. 13), had thefollowing characteristics d-spacing ranges and intensities:

TABLE 2 UZSi-9 d(Å) I 5.9-6.7 m 5.3-6.1 m-s 2.7-3.5 vs 2.0-2.8 w-m1.6-2.4 w

The formation of zirconium silicate involves the reaction of sodiumsilicate and zirconium acetate in the presence of sodium hydroxide andwater. The reaction has typically been conducted in small reactionvessels on the order of 1-5 Gallons. The smaller reaction vessels havebeen used to produce various crystalline forms of zirconium silicateincluding ZS-9. The inventors recognized that the ZS-9 being produced inthese smaller reactors had an inadequate or undesirably low cationexchange capacity (CEC).

The inventors have discovered that the use and proper positioning of abaffle-like structure in relation to the agitator within thecrystallization vessel produces a UZSi-9 crystal product exhibitingcrystalline purity (as shown by XRD and FTIR spectra) and anunexpectedly high potassium exchange capacity. In smaller scale reactors(5-gal), cooling coils were positioned within the reactor to provide abaffle-like structure. The cooling coils were not used for heatexchange. Several types of cooling coils are available and the differentdesigns may have some effect on the results presented herein, but theinventors used serpentine-type coils which snake along the inside wallof the reactor vessel.

The inventors found that the crystallization reaction used to produceUZSi-9 particularly benefited from baffles that when they are properlypositioned relative to the agitator. The inventors initially producedUZSi-9 with significant levels of undesirable UZSi-11 impurity. SeeFIGS. 10-11. This incomplete reaction is believed to have resulted fromsignificant amounts of solids remaining near the bottom of the reactionvessel. These solids near the bottom of the vessel remain even withconventional agitation. When properly positioned, the baffles andagitator improved the reaction conditions by creating forces within thereactor that lift the crystals within the vessel allowing for thenecessary heat transfer and agitation to make a high purity form ofUZSi-9. FIGS. 11-12 show XRD and FTIR spectra of high purity UZSi-9crystals. As shown in Table 3 below, these crystals exhibitsignificantly higher levels of potassium exchange capacity (KEC) thanthe less pure ZS-9 compositions. In an embodiment of the invention, theUZSi-9 crystals had a potassium exchange capacity of greater than 2.5meq/g, more preferably greater than 3.5 meq/g, more preferably greaterthan 4.0 meq/g, more preferably between 4.3 and 4.8 meq/g, even morepreferably between 4.4 and 4.7 meq/g, and most preferably approximately4.5 meq/g. UZSi-9 crystals having a potassium exchange capacity in therange of 3.7-3.9 were produced in accordance with Example 13 below.

Another unexpected benefit that came from using the reactor having astandard agitator in combination with baffles is that the highcrystalline purity, high potassium exchange capacity ZS-9 crystals couldbe produced without utilizing any seed crystals. Prior attempts atmaking homogenous crystals having high crystalline purity of a singlecrystalline form have utilized seed crystals. The ability to eliminatethe use of seed crystals was therefore an unexpected improvementrelative to prior art processes.

As stated the microporous compositions of this invention have aframework structure of octahedral ZrO₃ units, at least one oftetrahedral SiO₂ units and tetrahedral GeO₂ units, and optionallyoctahedral MO₃ units. This framework results in a microporous structurehaving an intracrystalline pore system with uniform pore diameters,i.e., the pore sizes are crystallographically regular. The diameter ofthe pores can vary considerably from about 3 angstroms and larger.

As synthesized, the microporous compositions of this invention willcontain some of the alkali metal templating agent in the pores. Thesemetals are described as exchangeable cations, meaning that they can beexchanged with other (secondary) A′ cations. Generally, the Aexchangeable cations can be exchanged with A′ cations selected fromother alkali metal cations (K⁺, Na⁺, Rb⁺, Cs⁺), alkaline earth cations(Mg²⁺, Ca²⁺, Sr²⁺, Ba²⁺), hydronium ion or mixtures thereof. It isunderstood that the A′ cation is different from the A cation. Themethods used to exchange one cation for another are well known in theart and involve contacting the microporous compositions with a solutioncontaining the desired cation (usually at molar excess) at exchangeconditions. Typically, exchange conditions include a temperature ofabout 25° C. to about 100° C. and a time of about 20 minutes to about 2hours. The use of water to exchange ions to replace sodium ions withhydronium ions may require more time, on the order of eight to tenhours. The particular cation (or mixture thereof) which is present inthe final product will depend on the particular use and the specificcomposition being used. One particular composition is an ion exchangerwhere the N cation is a mixture of Na⁺, Ca⁺² and H⁺ ions.

When ZS-9 is formed according to these processes, it can be recovered inthe Na-ZS-9 form. The sodium content of Na-ZS-9 is approximately 12 to13% by weight when the manufacturing process is carried out at pHgreater than 9. The Na-ZS-9 is unstable in concentrations ofhydrochloric acid (HCl) exceeding 0.2 M at room temperature, and willundergo structural collapse after overnight exposure. While ZS-9 isslightly stable in 0.2 M HCl at room temperature, at 37° C. the materialrapidly loses crystallinity. At room temperature, Na-ZS-9 is stable insolutions of 0.1M HCl and/or a pH of between approximately 6 to 7. Underthese conditions, the Na level is decreased from 13% to 2% uponovernight treatment.

The conversion of Na-ZS-9 to H-ZS-9 may be accomplished through acombination of water washing and ion exchange processes, i.e., ionexchange using a dilute strong acid, e.g., 0.1 M HCl or by washing withwater. Washing with water will decrease the pH and protonate asignificant fraction of the zirconium silicate, thereby lowering theweight fraction of Na in the zirconium silicate. It may be desirable toperform an initial ion exchange in strong acid using higherconcentrations, so long as the protonation of the zirconium silicatewill effectively keep the pH from dropping to levels at which thezirconium silicate decomposes. Additional ion exchange may beaccomplished with washing in water or dilute acids to further reduce thelevel of sodium in the zirconium silicate. The zirconium silicate madein accordance with the present invention exhibits a sodium content ofbelow 12% by weight. Preferably, the sodium contents is below 9% byweight, more preferably the sodium content is below 6% by weight, morepreferably the sodium content is below 3% by weight, more preferably thesodium content is in a range of between 0.05 to 3% by weight, and mostpreferably 0.01% or less by weight or as low as possible.

The ion exchanger in the sodium form, e.g., Na-ZS-9, is effective atremoving excess potassium ions from a patient's gastrointestinal tractin the treatment of hyperkalemia. When the sodium form is administeredto a patient, hydronium ions replace sodium ions on the exchangerleading to an unwanted rise in pH in the patient's stomach andgastrointestinal tract. Through in vitro tests it takes approximatelytwenty minutes in acid to stabilize sodium ion exchanger.

The hydronium form typically has equivalent efficacy as the sodium formfor removing potassium ions in vivo while avoiding some of thedisadvantages of the sodium form related to pH changes in the patient'sbody. For example, the hydrogenated form has the advantage of avoidingexcessive release of sodium in the body upon administration. This canmitigate edema resulting from excessive sodium levels, particularly whenused to treat acute conditions. Further, patient who are administeredthe hydronium form to treat chronic conditions will benefit from thelower sodium levels, particularly patients at risk for congestive heartfailure. Further, it is believed that the hydronium form will have theeffect of avoiding an undesirable increase of pH in the patient's urine.

The ZS-9 crystals have a broad particle size distribution. It has beentheorized that small particles, less than 3 microns in diameter, couldpotentially be absorbed into a patient's bloodstream resulting inundesirable effects such as the accumulation of particles in the urinarytract of the patient, and particularly in the patient's kidneys. Thecommercially available zirconium silicates are manufactured in a waythat some of the particles below 1 micron are filtered out. However, ithas been found that small particles are retained in the filter cake andthat elimination of particles having a diameter less than 3 micronsrequires the use of additional screening techniques.

The inventors have found that screening can be used to remove particleshaving a diameter below 3 microns and that removal of such particles isbeneficial for therapeutic products containing the zirconium silicatecompositions of the invention. Many techniques for particle screeningcan be used to accomplish the objectives of the invention, includinghand screening, air jet screening, sifting or filtering, floating or anyother known means of particle classification. Zirconium silicatecompositions that have been subject to screening techniques exhibit adesired particle size distribution that avoids potential complicationsinvolving the therapeutic use of zirconium silicate. In general, thesize distribution of particles is not critical, so long as excessivelysmall particles are removed. The zirconium silicate compositions of theinvention exhibit a median particle size greater than 3 microns, andless than 7% of the particles in the composition have a diameter lessthan 3 microns. Preferably, less than 5% of the particles in thecomposition have a diameter less than 3 microns, more preferably lessthan 4% of the particles in the composition have a diameter less than 3microns, more preferably less than 3% of the particles in thecomposition have a diameter of less than 3 microns, more preferably lessthan 2% of the particles in the composition have a diameter of less than3 microns, more preferably less than 1% of the particles in thecomposition have a diameter of less than 3 microns, more preferably lessthan 0.5% of the particles in the composition have a diameter of lessthan 3 microns. Most preferably, none of the particles or only traceamounts have a diameter of less than 3 microns. The median particle sizeis preferably greater than 3 microns and particles reaching a sizes onthe order of 1,000 microns are possible for certain applications.Preferably, the median particle size ranges from 5 to 1000 microns, morepreferably 10 to 600 microns, more preferably from 15 to 200 microns,and most preferably from 20 to 100 microns.

The particle screening can be conducted before, during, or after an ionexchange process such as described above whereby the sodium content ofthe zirconium silicate material is lowered below 12%. The lowering ofsodium content to below 3% can occur over several steps in conjunctionwith screening or can occur entirely before or after the screening step.Particles having a sodium content below 3% may be effective with orwithout screening of particles sizes as described herein.

In addition to screening or sieving, the desired particle sizedistribution may be achieved using a granulation or other agglomerationtechnique for producing appropriately sized particles.

It is also within the scope of the invention that these microporous ionexchange compositions can be used in powder form or can be formed intovarious shapes by means well known in the art. Examples of these variousshapes include pills, extrudates, spheres, pellets and irregularlyshaped particles.

As stated, these compositions have particular utility in adsorbingvarious toxins from fluids selected from bodily fluids, dialysatesolutions, and mixtures thereof. As used herein, bodily fluids willinclude but not be limited to blood and gastrointestinal fluids. Also bybodily is meant any mammalian body including but not limited to humans,cows, pigs, sheep, monkeys, gorillas, horses, dogs, etc. The instantprocess is particularly suited for removing toxins from a human body.

The zirconium metallates can also be formed into pills or other shapeswhich can be ingested orally and pickup toxins in the gastrointestinalfluid as the ion exchanger transits through the intestines and isfinally excreted. In order to protect the ion exchangers from the highacid content in the stomach, the shaped articles may be coated withvarious coatings which will not dissolve in the stomach, but dissolve inthe intestines.

As has also been stated, although the instant compositions aresynthesized with a variety of exchangeable cations (“A”), it ispreferred to exchange the cation with secondary cations (A′) which aremore compatible with blood or do not adversely affect the blood. Forthis reason, preferred cations are sodium, calcium, hydronium andmagnesium. Preferred compositions are those containing sodium andcalcium or sodium, calcium and hydronium ions. The relative amount ofsodium and calcium can vary considerably and depends on the microporouscomposition and the concentration of these ions in the blood. Asdiscussed above, when sodium is the exchangeable cation, it is desirableto replace the sodium ions with hydronium ions thereby reducing thesodium content of the composition.

The compositions of the present invention may be used in the treatmentof hyperkalemia comprising administering the composition to a patient inneed thereof. The administered dose may vary, depending on whether thetreatment is for chronic or acute hyperkalemia. The dose for treatingacute hyperkalemia is higher than that for the treatment of chronichyperkalemia. For the treatment of acute hyperkalemia, the dosepreferably ranges from approximately 0.7 to 1,500 mg/Kg/day, morepreferably from approximately 500 to 1,000 mg/Kg/day, and mostpreferably approximately 700 mg/Kg/day. A typical daily dose fortreatment of acute hyperkalemia, depending on the potassium exchangecapacity, in a human patient will range from approximately 50 mg to 60 gper day, more preferably from approximately 1 mg to 30 g per day, morepreferably 3 to 9 g per day, and most preferably approximately 3 g perday. For the treatment of chronic hyperkalemia, the dose preferablyranges from 0.25 to 100 mg/Kg/day, more preferably from 10 to 70mg/Kg/day, and most preferably approximately 50 mg/Kg/day. A typicaldaily dose for treatment of chronic hyperkalemia in a human patient willrange from approximately 0.020 to 10 g per day, more preferably from 0.1to 1 g per day, and most preferably approximately 0.5 g per day.

For higher KEC compositions, the dosages will typically be lower due tothe increased effectiveness of the compositions for lowering potassiumlevels in a patient. For the treatment of acute hyperkalemia, the dosepreferably ranges from approximately 0.7 to 800 mg/Kg/day, morepreferably from approximately 280 to 500 mg/Kg/day, and most preferablyapproximately 390 mg/Kg/day. A typical daily dose for treatment of acutehyperkalemia, depending on the potassium exchange capacity, in a humanpatient will range from approximately 50 mg to 33 g per day, morepreferably from approximately 1 mg to 30 g per day, more preferably 3 to9 g per day, and most preferably approximately 3 g per day. For thetreatment of chronic hyperkalemia, the dose preferably ranges from 0.25to 55 mg/Kg/day, more preferably from 5 to 40 mg/Kg/day, and mostpreferably approximately 30 mg/Kg/day. A typical daily dose fortreatment of chronic hyperkalemia in a human patient will range fromapproximately 0.020 to 5 g per day, more preferably from 0.05 to 0.7 gper day, and most preferably approximately 0.5 g per day.

In order to more fully illustrate the invention, the following examplesare set forth. It is to be understood that the examples are only by wayof illustration and are not intended as an undue limitation on the broadscope of the invention as set forth in the appended claims.

EXAMPLE 1

A solution was prepared by mixing 2058 g of colloidal silica (DuPontCorp. identified as Ludox™ AS-40), 2210 g of KOH in 7655 g H₂O. Afterseveral minutes of vigorous stirring 1471 g of a zirconium acetatesolution (22.1 wt. % ZrO₂) were added. This mixture was stirred for anadditional 3 minutes and the resulting gel was transferred to astainless steel reactor and hydrothermally reacted for 36 hours at 200°C. The reactor was cooled to room temperature and the mixture was vacuumfiltered to isolate solids which were washed with deionized water anddried in air.

The solid reaction product was analyzed and found to contain 21.2 wt. %Si, 21.5 wt. % Zr, K 20.9 wt. % K, loss on ignition (LOI) 12.8 wt. %,which gave a formula of K_(2.3)ZrSi_(3.2)O_(9.5)*3.7H₂O. This productwas identified as sample A.

EXAMPLE 2

A solution was prepared by mixing 121.5 g of colloidal silica (DuPontCorp. identified as Ludox® AS-40), 83.7 g of NaOH in 1051 g H₂O. Afterseveral minutes of vigorous stirring 66.9 g zirconium acetate solution(22.1 wt. % ZrO₂) was added. This was stirred for an additional 3minutes and the resulting gel was transferred to a stainless steelreactor and hydrothermally reacted with stirring for 72 hours at 200° C.The reactor was cooled to room temperature and the mixture was vacuumfiltered to isolate solids which were washed with deionized water anddried in air.

The solid reaction product was analyzed and found to contain 22.7 wt. %Si, 24.8 wt. % Zr, 12.8 wt. % Na, LOI 13.7 wt. %, which gives a formulaNa_(2.0)ZrSi_(3.0)O_(9.0)*3.5H₂O. This product was identified as sampleB.

EXAMPLE 3

A solution (60.08 g) of colloidal silica (DuPont Corp. identified asLudox® AS-40) was slowly added over a period of 15 minutes to a stirringsolution of 64.52 g of KOH dissolved in 224 g deionized H₂O. This wasfollowed by the addition of 45.61 g zirconium acetate (Aldrich 15-16 wt.% Zr, in dilute acetic acid). When this addition was complete, 4.75 ghydrous Nb₂O₅ (30 wt. % LOI) was added and stirred for an additional 5minutes. The resulting gel was transferred to a stirred autoclavereactor and hydrothermally treated for 1 day at 200° C. After this time,the reactor was cooled to room temperature, the mixture was vacuumfiltered, the solid washed with deionized water and dried in air.

The solid reaction product was analyzed and found to contain 20.3 wt. %Si, 15.6 wt. % Zr, 20.2 wt. % K, 6.60 wt. % Nb, LOI 9.32 wt. %, whichgive a formula of K_(2.14)Zr_(0.71)Nb_(0.29)Si₃O_(9.2)*2.32H₂O. ScanningElectron (SEM) of a portion of the sample, including EDAX of a crystal,indicated the presence of niobium, zirconium, and silicon frameworkelements. This product was identified as sample C.

EXAMPLE 4

To a solution prepared by mixing 141.9 g of NaOH pellets in 774.5 g ofwater, there were added 303.8 g of sodium silicate with stirring. Tothis mixture there were added dropwise, 179.9 g of zirconium acetate(15% Zr in a 10% acetic acid solution). After thorough blending, themixture was transferred to a Hastalloy™ reactor and heated to 200° C.under autogenous pressure with stirring for 72 hours. At the end of thereaction time, the mixture was cooled to room temperature, filtered andthe solid product was washed with a 0.001M NaOH solution and then driedat 100° C. for 16 hours. Analysis by x-ray powder diffraction showedthat the product was pure ZS-11.

EXAMPLE 5

To a container there was added a solution of 37.6 g NaOH pelletsdissolved in 848.5 g water and to this solution there were added 322.8 gof sodium silicate with mixing. To this mixture there were addeddropwise 191.2 g of zirconium acetate (15% Zr in 10% acetic acid). Afterthorough blending, the mixture was transferred to a Hastalloy™ reactorand the reactor was heated to 200° C. under autogenous conditions withstirring for 72 hours. Upon cooling, the product was filtered, washedwith 0.001M NaOH solution and then dried at 100° C. for 16 hours. X-raypowder diffraction analysis showed the product to be ZS-9.

EXAMPLE 6

Approximately 57 g (non-volatile-free basis, lot 0063-58-30) of Na-ZS-9was suspended in about 25 mL of water. A solution of 0.1N HCl was addedgradually, with gentle stirring, and pH monitored with a pH meter. Atotal of about 178 milliliters of 0.1N HCl was added with stirring, themixture filtered then further rinsed with additional 1.2 liters 0.1N HClwashes. The material was filtered, dried and washed with DI water. ThepH of the resulting material was 7.0. The H-ZS-9 powder resulting fromthis three batch-wise ion exchange with 0.1N HCl has <12% Na.

As illustrated in this example, batch-wise ion exchange with a dilutestrong acid is capable of reducing the sodium content of a NA-ZS-9composition to within a desired range.

EXAMPLE 7

Approximately 85 gram (non-volatile-free basis, lot 0063-59-26) ofNa-ZS-9 was washed with approximately 31 Liters of DI water at 2 Literincrements over 3 days until the pH of the rinsate reached 7. Thematerial was filtered, dried and washed with DI water. The pH of theresulting material was 7. The H-ZS-9 powder resulting from batch-wiseion exchange and water wash has <12% Na.

As illustrated in this example, water washing is capable of reducing thesodium content of a NA-ZS-9 composition to within a desired range.

EXAMPLE 8

Separate batches of ZS-9 crystals were analyzed using light scatterdiffraction techniques. The particle size distribution and othermeasured parameters are shown in FIGS. 2-4. The d(0.1), d(0.5), andd(0.9) values represent the 10%, 50%, and 90% size values. Thecumulative particle size distribution is shown in FIG. 4-6. As can beseen from the following figures, the cumulative volume of particleshaving a diameter below 3 microns ranges from approximately 0.3% toapproximately 6%. In addition, different batches of ZS-9 have differentparticle size distributions with varying levels of particles having adiameter of less than 3 microns.

EXAMPLE 9

Crystals of ZS-9 were subject to screening to remove small diameterparticles. The resulting particle size distribution of the ZS-9 crystalsscreened using different size screens was analyzed. As illustrated inthe following figures, the fraction of particles having a diameter below3 microns can be lowered and eliminated using an appropriate mesh sizescreen. Without screening, approximately 2.5% percent of the particleshad a diameter of below 3 microns. See FIG. 5. Upon screening with a 635mesh screen, the fraction of particles having a diameter below 3 micronswas reduced to approximately 2.4%. See FIG. 6. Upon screening with a 450mesh screen, the fraction of particles having a diameter below 3 micronswas reduced further to approximately 2%. See FIG. 7. When a 325 meshscreen is used, the fraction of particles having a diameter below 3microns is further reduced to approximately 0.14%. See FIG. 8. Finally,a 230 mesh screen reduces the fraction of particles below 3 microns to0%. See FIG. 9.

The screening techniques presented in this example illustrate thatparticle size distributions may be obtained for ZS-9 that provide littleor no particles below 3 microns. It will be appreciated that ZS-9according to Example 5 or H-ZS-9 according to Examples 6 and 7 may bescreened as taught in this example to provide a desired particle sizedistribution. Specifically, the preferred particle size distributionsdisclosed herein may be obtained using the techniques in this examplefor both ZS-9 and H-ZS-9.

EXAMPLE 10

A 14-Day repeat dose oral toxicity study in Beagle Dogs with Recoverywas conducted. This GLP compliant oral toxicity study was performed inbeagle dogs to evaluate the potential oral toxicity of ZS-9 whenadministered at 6 h intervals over a 12 h period, three times a day, infood, for at least 14 consecutive days. In the Main Study ZS-9 wasadministered to 3/dogs/sex/dose at dosages of 0 (control), 325, 650 or1300 mg/kg/dose. An additional 2 dogs/sex/dose, assigned to the RecoveryStudy, received 0 or 1300 mg/kg/dose concurrently with the Main studyanimals and were retained off treatment for an additional 10 days. Acorrection factor of 1.1274 was used to correct ZS-9 for water content.Dose records were used to confirm the accuracy of dose administration.

During the acclimation period (Day −7 to Day −1) dogs were trained toeat 3 portions of wet dog chow at 6 h intervals. During treatment therequisite amount of test article (based on the most recently recordedbody weight) was mixed with ˜100 g of wet dog food and offered to thedogs at 6 h intervals. Additional dry food was offered followingconsumption of the last daily dose. Each dog received the same amount ofwet dog feed. Body weights were recorded at arrival and on Days −2, −1,6, 13 and 20. Clinical observations were performed twice daily duringthe acclimation, treatment and recovery periods. Wet and dry foodconsumption was measured daily during the treatment period. Blood andurine samples for analysis of serum chemistry, hematology, coagulationand urinalysis parameters were collected pretest (Day −1) and Day 13.Ophthalmologic examinations were performed pretest (Day −6/7) and on Day7 (females) or 8 (males). Electrocardiographic assessments wereperformed pretest (Day −1) and on Day 11. At study termination (Day14—Main Study and Day 24—Recovery Study), necropsy examinations wereperformed, protocol specified organ weights were weighed, and selectedtissues were microscopically examined.

Oral administration of 325, 650 and 1300 mg ZS-9/kg/dose with food,three times a day at 6 h intervals over a 12-hour period for 14 days waswell tolerated. Clinical signs were limited to the observation of whitematerial, presumed to be test article, in the feces of some dogs at the325 mg/kg/dose and in all animals receiving 650 mg/kg/dose during thesecond week of treatment. There were no adverse effects on body weight,body weight change, food consumption, hematology and coagulationparameters or ophthalmoscopic and ECG evaluations.

There were no macroscopic findings associated with administration ofZS-9. Microscopically, minimal to mild focal and/or multifocalinflammation was observed in the kidneys of treated animals but not inControl animals. The lesions had similar incidence and severity at 650and 1300 mg/kg and were less frequent and severe at 325 mg/kg. In somedogs the inflammation was unilateral rather than bilateral and in somecases was associated with inflammation in the urinary bladder and originof the ureter. Taken together these observations suggest that factorsother than direct renal injury, such as alterations in urine compositionof ZS-9-treated dogs may have resulted in increased susceptibility tosubclinical urinary tract infections, even though no microorganisms wereobserved in these tissues. In recovery animals the inflammation wascompletely resolved in females and partly resolved in males suggestingthat whatever the cause of the inflammation it was reversible followingcessation of dosing. The increased incidence of mixed leukocyteinflammation observed in Beagle dogs treated with ZS-9 is summarizedbelow.

Summary of Inflammation in Kidneys Terminal Necropsy (TN): Day 14 Dose 0mg/kg 325 mg/kg 650 mg/kg 1,300 mg/kg Sex M F M F M F M F Number ofAnimals 3 3 3 3 3 3 3 3 Left Incidence 0/3 0/3 0/3 2/3 2/3 3/3 3/3 3/3Kidney minimal 0/3 0/3 0/3 2/3 2/3 2/3 3/3 1/3 mild 0/3 0/3 0/3 0/3 0/31/3 0/3 2/3 Right Incidence 0/3 0/3 1/3 1/3 2/3 3/3 2/3 2/3 Kidneyminimal 0/3 0/3 1/3 1/3 2/3 1/3 2/3 0/3 mild 0/3 0/3 0/3 0/3 0/3 2/3 0/32/3 Both Incidence 0/6 0/6 1/6 3/6 4/6 6/6 5/6 5/6 Kidneys minimal 0/60/6 1/6 3/6 4/6 3/6 5/6 1/6 mild 0/6 0/6 0/6 0/6 0/6 3/6 0/6 4/6 Sum ofSeverity Scores 0 0 2 3 4 9 5 9 0 5 13 14 Mean Group Severity 0.00 0.832.17 2.33 Scores

Minimal acute urinary bladder inflammation and unidentified crystalswere also observed in the renal pelvis and urine of females dosed at 650mg/kg/dose as summarized below

Summary of Crystals observed at the 650 mg/kg/dose Animal No 4420 44214422 Unidentified crystals + − + in urine Crystals in renal pelvis − + −Urinary bladder + + − acute inflammation

Crystals were not identified in group 2 or 4 females or in any ZS-9treated males.

In both studies it was noted that urinary pH was elevated compared tocontrol and it was postulated that the change in urinary pH and/orurinary composition affected urine solute solubility resulting incrystal formation that caused urinary tract irritation and/or increasedsusceptibility to urinary tract infections (UTIs).

The description of the urinary crystals (long thin spiky clusters)coupled with the particle size profile and insolubility of test articlemake it very unlikely that these crystals are ZS-9.

EXAMPLE 11

Crystals of ZS-9 are prepared and designated “ZS-9 Unscreened.”Screening in accordance with the procedures of Example 10 is conductedon a sample of ZS-9 crystals and the screened sample is designated“ZS-9>5 μm.” Another sample of Crystals of ZS-9 undergo an ion exchangein accordance with the procedures of Example 6 above and are thenscreened in accordance with the procedures of Example 10. The resultingH-ZS-9 crystals are designated “ZS-9+>5 μm.”

The following 14-day study is designed to show the effect of particlesize and particle form on the urinary pH and presence of crystals in theurine. The compounds above are administered to beagles orally by mixingwith wet dog food. The regimen is administered 3 times a day at 6 hourintervals over a 12 hour period in the following manner:

Study Design

Group mg/kg/dose* Female Control 0 3 ZS-9 Unscreened 750 3 ZS-9 >5 μm750 3 ZS-9 + >5 μm 750 3 ZS-9 Unscreened 100 3 ZS-9 >5 μm 100 3ZS-9 + >5 μm 100 3 NaHCO₃ 50 3 *uncorrected for water ZS-9+ = pH neutralcrystal Total number of dogs 24 females Age 5 months of age on arrivalAcclimation ≧10 days Test Article Formulation Mixed with wet dog foodTest article administration Within 30 minutes of administration DoseFormulation Analysis Dose records will be used to confirm dosing. Weightof any remaining wet food will be recorded.

The following table outlines the observations, toxicokinetic evaluation,laboratory investigation (hematology, urinalysis), and terminalprocedures.

Observations Mortality & Signs of ill Twice daily (after treatment andevening) health or reaction to treatment including feces assessmentDetailed Exam During acclimation, weekly on study Body Weights Arrival,Day −1, Day 7 and 14 Food Consumption Daily (Wet and Dry food)Ophthalmoloscopy None Toxicokinetic (for potential Zr analysis) 3 × 1 mlwhole blood/sample Day −1: Pre-dose with sample weights recorded Day 13:Pre-dose and 4 h post 2^(nd) dose Laboratory InvestigationsHematology/Clinical Pretreatment and during Weeks 1 and 2 chemistry (seelist) on study Urinalysis Pretreatment and during Weeks 1 and 2 on (seelist) study (Metabolic cage, urine sample to be kept cool) Remainingurine aliquoted and retained frozen for possible future Zr analysisTerminal Procedures Necropsy All animals regardless of mode of death.All tissues collected into NBF (see list) Histopathology Urinary tractonly (Kidney and bladder)

These tests show that the zirconium silicates of the present inventionare particularly suitable for the treatment of hyperkalemia.

EXAMPLE 12

UZSi-9 crystals were prepared by reaction in a standard 5-Gcrystallization vessel.

The reactants were prepared as follows. A 22-L Morton flask was equippedwith an overhead stirrer, thermocouple, and an equilibrated additionfunnel. The flask was charged with deionized water (3.25 L). Stirringwas initiated at approximately 100 rpm and sodium hydroxide (1091 gNaOH) was added to the flask. The flask contents exothermed as thesodium hydroxide dissolved. The solution was stirred and cooled to lessthan 34° C. Sodium silicate solution (5672.7 g) was added. To thissolution was added zirconium acetate solution (3309.5 g) over 43minutes. The resulting suspension was stirred for another 22 minutes.Seed crystals of ZS-9 (223.8 g) were added to the reaction vessel andstirred for approximately 17 minutes.

The mixture was transferred to a 5-G Parr pressure vessel with the aidof deionized water (0.5 L). The vessel had smooth walls and a standardagitator. The reactor did not have a cooling coil present. The vesselwas sealed and the reaction mixture was stirred at approximately 275-325rprn and heated to 185+/−10° C. over 4 hours, then held at 184-186° C.and soaked for 72 hours. Finally, the reactants were then cooled to 80°C. over 12.6 hours. The resulting white solid was filtered with the aidof deionized water (18 L). The solids were washed with deionized water(125 L) until the pH of the eluting filtrate was less than 11 (9.73).The wet cake was dried in vacuo (25 inches Hg) for 48 hours at 95-105°C. to give 2577.9 g (107.1%) of ZS-9 as a white solid.

The XRD plot of the ZS-9 obtained in this example is shown in FIG. 10.The FTIR plot of this material is shown in FIG. 11. These XRD and FTIRspectra are characterized by the presence of absorption peaks typicallyassociated with the ZS-11 crystalline form. In addition, the peaks thatare associated with ZS-9 exhibit significant spreading due to crystalimpurities (e.g. the presence of ZS-11 crystals in a ZS-9 composition).For example, the FTIR spectra shows significant absorption around 764and 955 cm⁻¹. The XRD plot for this example exhibits significant noiseand poorly defined peaks at 2-theta values of 7.5, 32, and 42.5.

EXAMPLE 13

High capacity UZSi-9 crystals were prepared in accordance with thefollowing representative example.

The reactants were prepared as follows. A 22-L Morton flask was equippedwith an overhead stirrer, thermocouple, and an equilibrated additionfunnel. The flask was charged with deionized water (8,600 g, 477.37moles). Stirring was initiated at approximately 145-150 rpm and sodiumhydroxide (661.0 g, 16.53 moles NaOH, 8.26 moles Na20) was added to theflask. The flask contents exothermed from 24° C. to 40° C. over a periodof 3 minutes as the sodium hydroxide dissolved. The solution was stirredfor an hour to allow the initial exotherm to subside. Sodium silicatesolution (5,017 g, 22.53 mole SO2, 8.67 moles Na20) was added. To thissolution, by means of the addition funnel, was added zirconium acetatesolution (2,080 g, 3.76 moles Zr02) over 30 min. The resultingsuspension was stirred for and additional 30 min.

The mixture was transferred to a 5-G Parr pressure vessel Model 4555with the aid of deionized water (500 g, 27.75 moles). The reactor wasfitted with a cooling coil having a serpentine configuration to provideda baffle-like structure within the reactor adjacent the agitator. Thecooling coil was not charged with heat exchange fluid as it was beingused in this reaction merely to provide a baffle-like structure adjacentthe agitator.

The vessel was sealed and the reaction mixture was stirred atapproximately 230-235 rprn and heated from 21° C. to 140-145° C. over7.5 hours and held at 140-145° C. for 10.5 hours, then heated to210-215° C. over 6.5 hours where the maximum pressure of 295-300 psi wasobtained, then held at 210-215° C. for 4 1.5 hours. Subsequently, thereactor was cooled to 45° C. over a period of 4.5 hours. The resultingwhite solid was filtered with the aid of deionized water (1.0 KG). Thesolids were washed with deionized water (40 L) until the pH of theeluting filtrate was less than 11 (10.54). A representative portion ofthe wet cake was dried in vacuo (25 inches Hg) overnight at 100° C. togive 1,376 g (87.1%) of ZS-9 as a white solid.

The XRD plot of the ZS-9 obtained is shown in FIG. 12. The FTIR plot ofthis material is shown in FIG. 13. These XRD and FTIR spectra, whencompared to those for Example 12 (FIGS. 10-11), exhibitedwell-delineated peaks without spreading and the absence of peaksassociated with crystalline forms other than ZS-9 (e.g., ZS-11 peaks).This example illustrates how the presence of a baffle-like structurewithin the reactor drastically and unexpectedly improves the quality ofthe thus obtained crystals. Although not wishing to be bound by theory,the inventors understand that baffles provide added turbulence whichlifts the solids (i.e., crystals) and results in a more even suspensionof crystals within the reaction vessel while the reaction is ongoing.This improved suspension allows for more complete reaction to thedesired crystalline form and reduces the presence of unwantedcrystalline forms of zirconium silicate in the end product.

EXAMPLE 14

The potassium exchange capacity (KEC) of zirconium silicate (ZS-9) wasdetermined according to the following protocol.

This test method used a HPLC capable of gradient solvent introductionand cation exchange detection. The column was an IonPac CS12A,Analytical (2×250 mm). The flow rate was 0.5 mL/minute with a run timeof approximately 8 minutes. The column temperature was set to 35° C. Theinjection volume was 10 μL and the needle wash was 250 μL. The pump wasoperated in Isocratic mode and the solvent was DI water.

A stock standard was prepared by accurately weighing and recording theweight of about 383 mg of potassium chloride (ACS grade), which wastransferred into a 100-mL plastic volumetric flask. The material wasdissolved and diluted to volume with diluent followed by mixing. Thestock standard had a K⁺ concentration of 2000 ppm (2 mg/mL). Sampleswere prepared by accurately weighing, recording, and transferring about112 mg of ZS-9 into a 20 mL plastic vial. 20.0 mL of the 2000 ppmpotassium stock standard solution was pipetted into the vial and thecontainer was closed. The sample vials were placed onto a wrist actionshaker and were shook for at least 2 hours but not more than 4 hours.The sample preparation solution was filtered through a 0.45 pm PTFEfilter into a plastic container. 750 pL of the sample solution wastransferred into a 100-mL plastic volumetric flask. The sample wasdiluted to volume with DI water and mixed. The initial K⁺ concentrationwas 15 ppm (1 SpgImL).

The samples were injected into the HPLC. FIG. 14 shows an example of theblank solution chromatogram. FIG. 15 shows an example of the assaystandard solution chromatogram. FIG. 16 shows an exemplary samplechromatogram. The potassium exchange capacity was calculated using thefollowing formula:

${KEC} = \frac{\frac{\left( {{IC} - {FC}} \right) \times V}{{Eq}\mspace{14mu}{{wt}.}}}{{{Wt} \cdot_{SPL}} \times \frac{{100\%} - {\%\mspace{14mu}{Water}}}{100\%} \times \frac{1\mspace{14mu} g}{1000\mspace{14mu}{mg}}}$KEC is the potassium exchange capacity in mEq/g. The initialconcentration of potassium (ppm) is IC. The final concentration ofpotassium (ppm) is FC. The equivalent weight (atomic weight/valence) isEq wt. The volume (L) of standard in sample preparation is V. The weightof ZS-9 (mg) used for sample preparation is Wt_(spl). The percent (%) ofwater content (LOD) is % water.

Three samples of ZS-9 produced in accordance with the procedures ofExample 12, i.e., in a reactor without baffles (e.g., internal coolingcoil structure), were tested for potassium exchange capacity (KEC) inaccordance with the above-referenced procedure. Likewise, three samplesof ZS-9 produced in accordance with Example 13 in a reactor havingcooling coils serving as baffles were tested in accordance with thisprocedure. The results in Table 3 below show that the procedure ofExample 13 and the presence of baffles within the crystallization vesselresulted in a dramatic increase in the potassium exchange capacity.

TABLE 3 Potassium Exchange Capacity (KEC) Example 12 (Without baffles)Example 13 (With baffles) Lot 5368-10311A 2.3 meq/gm Lot 2724-9A 3.9meq/gm Lot 5368-12211A 1.7 meq/gm Lot 2724-13D 3.8 meq/gm Lot5368-13811A 1.8 meq/gm Lot 2724-18F 3.8 meq/gm

EXAMPLE 15

The use of an internal cooling coil to provide a baffle-like structurewithin the reactor is only feasible for small reactors on the order of5-gallons because larger reactors cannot be easily fitted with, andtypically do not utilized, cooling coils.

The inventors have designed a reactor for larger-scale production ofhigh purity, high-KEC ZS-9 crystals. Large-scale reactors typicallyutilize a jacket for achieving heat transfer to the reaction chamberrather than coils suspended within the reaction chamber. A conventional200-L reactor 100 is shown in FIG. 17. The reactor 100 has smooth wallsand an agitator 101 extending into the center of the reaction chamber.The reactor 100 also has a thermowell 102 and a bottom outlet valve 103.The inventors have designed an improved reactor 200, FIG. 18, which alsohas an agitator 201, thermowell 202, and bottom outlet valve 203. Theimproved reactor 200 has baffle structures 204 on its sidewalls, whichin combination with the agitator 201 provide significant lift andsuspension of the crystals during reaction and the creation of highpurity, high KEC ZS-9 crystals. The improved reactor can also include acooling or heating jacket for controlling the reaction temperatureduring crystallization in addition to the baffle structures 204. Thedetails of an exemplary and non-limiting baffle design is shown in FIG.19. Preferably the reactor has a volume of at least 20-L, morepreferably 200-L or more, or within the range of 200-L to 30,000-L.

Other embodiments and uses of the invention will be apparent to thoseskilled in the art from consideration of the specification and practiceof the invention disclosed herein. All references cited herein,including all U.S. and foreign patents and patent applications, arespecifically and entirely hereby incorporated herein by reference. It isintended that the specification and examples be considered exemplaryonly, with the true scope and spirit of the invention indicated by thefollowing claims.

The invention claimed is:
 1. A particulate cation exchange compositioncomprising a zirconium silicate of formula (I):A_(p)M_(x)Zr_(1-x)Si_(n)Ge_(y)O_(m)  (I), in the ZS-1 form, where A is apotassium ion, hydronium ion or mixtures thereof, M is at least oneframework metal, wherein the framework metal is hafnium (4+), tin (4+),niobium (5+), titanium (4+), cerium (4+), germanium (4+), praseodymium(4+), terbium (4+) or mixtures thereof, “p” has a value from about 1 toabout 20, “x” has a value from 0 to less than 1, “n” has a value fromabout 0 to about 12, “y” has a value from 0 to about 12, “m” has a valuefrom about 3 to about 36 and 1≦n+y≦12, wherein the particles exhibit auniform microporous structure and a median particle size of greater than3 microns and less than 7% of the particles in the composition have adiameter less than 3 microns.
 2. The composition of claim 1, wherein 4%of the particles in the composition have a diameter less than 3 microns.3. The composition of claim 1, wherein less than 1% of the particles inthe composition have a diameter less than 3 microns.
 4. The compositionof claim 1, wherein the median particle size ranges from 5 to 1000microns.
 5. The composition of claim 1, wherein the median particle sizeranges from 20 to 100 microns.
 6. The composition of claim 1, whereinthe zirconium silicate exhibits an X-ray powder diffraction patterngenerated using a copper K-alpha radiation source of: d(Å) 7.7-8.66.3-7.0 5.5-6.3 4.7-5.5 3.2-4.0 2.6-3.4.


7. The composition of claim 1, wherein the zirconium silicate isprotonated.
 8. A pharmaceutical composition product comprising thecomposition of claim 1 in capsule or tablet form.
 9. A particulatecation exchange composition comprising a zirconium silicate of formula(I):A_(p)M_(x)Zr_(1-x)Si_(n)Ge_(y)O_(m)  (I) in the ZS-9 form and in theZS-1 form where A is a potassium ion, hydronium ion or mixtures thereof,M is at least one framework metal, wherein the framework metal ishafnium (4+), tin (4+), niobium (5+), titanium (4+), cerium (4+),germanium (4+), praseodymium (4+), terbium (4+) or mixtures thereof, “p”has a value from about 1 to about 20, “x” has a value from 0 to lessthan 1, “n” has a value from about 0 to about 12, “y” has a value from 0to about 12, “m” has a value from about 3 to about 36 and 1≦n+y≦12,wherein the particles exhibit a uniform microporous structure and amedian particle size of greater than 3 microns and less than 7% of theparticles in the composition have a diameter less than
 3. 10. Thecomposition of claim 9, wherein the ZS-9 form exhibits an X-ray powderdiffraction pattern generated using a copper K-alpha radiation sourceof: d(Å) 5.9-6.7 5.3-6.1 2.7-3.5 2.0-2.8 1.6-2.4

and the ZS-1 form exhibits an X-ray powder diffraction pattern of: d(Å)7.7-8.6 6.3-7.0 5.5-6.3 4.7-5.5 3.2-4.0 2.6-3.4.


11. A pharmaceutical composition product comprising the composition ofclaim 9 in capsule or tablet form.
 12. A method of removing excess serumammonium ions comprising administering to a subject in need thereof anamount of the composition of claim
 1. 13. The method of claim 12,wherein the amount administered is a dose of approximately 0.7 to 1,500mg/Kg/day.
 14. The method of claim 12, wherein the amount administeredis a dose of approximately 500 to 1,000 mg/Kg/day.
 15. The method ofclaim 12, wherein the amount administered is a dose of approximately 700mg/Kg/day.
 16. The method of claim 12, wherein the subject also exhibitsexcess serum potassium levels.
 17. The method of claim 12, wherein theZS-1 is protonated.
 18. A method of treating hyperammonemia comprisingadministering to a subject in need thereof an effective amount of thecomposition of claim 1 to treat the subject.
 19. The method of claim 12,wherein the subject also suffers from hyperkalemia.
 20. The method ofclaim 19, wherein the hyperkalemia is acute hyperkalemia.
 21. The methodof claim 19, wherein the hyperkalemia is chronic or sub-acutehyperkalemia.
 22. The method of claim 12, further comprisingadministering a ZS-9.
 23. The method of claim 22, wherein the ZS-9exhibits a median particle size of greater than 3 microns and less than7% of the particles in the composition have a diameter less than 3microns, and the composition exhibits a sodium content below 12% byweight.